Local anesthetics comprising alpha-phenyl-alpha-alkylsuccinimides

ABSTRACT

NEW A-PHENYL-A-ALKYLSUCCINIMIDES SUBSTITUTED AT THE NITROGEN ATOM WITH AN ALKYLAMINOALKYL GROUP ARE DISCLOSED WHICH ARE EFFECTIVE AS LOCAL ANESTHETICS.

United States Patent 3,636,221 Patented Jan. 18, 1972 US. Cl. 424-274 19 Claims ABSTRACT OF THE DISCLOSURE New a-phenyl-a-alkylsuccinimides substituted at the nitrogen atom with an alkylaminoalkyl group are disclosed which are efiective as local anesthetics.

The present invention relates to N-alkyl aminoalkyl substituted u-phenyl-a-alkylsuccinimides and their salts and also to a process for their preparation as well as pharmaceutical preparations thereof.

More particularly the present invention relates to compounds of the formula wherein R is selected from the group consisting of saturated and unsaturated straight and branched lower alkyl with at most 6 carbon atoms; R is a bivalent saturated straight or branched hydrocarbon radical including carbocyclic bivalent groups containing at most 6 carbon atoms and Am is an amino group selected from the class consisting of 0H )m-R wherein R is a hydrogen atom or a straight or branched lower alkyl group, R is a hydrogen atom, a hydroxy or lower alkoxy group and m is 14 in cases when R is a hydrogen atom or 2, 3 or 4 in cases when R is a hydroxy or lower alkoxy group, and a process for their preparation.

Illustrative examples of compounds of the present invention are the following:

N- 3- (N-methyl-N-hydroxyethylamino) -propyl] a-phenyl-a-propylsuccinimide,

N- [3- (N'-methyl-N'-hydroxyethylamino)-propyl]- a-phenyl-u-pentylsuccinamide,

N- (3 -ethylaminopropyl -a-phenyl-a-n-prOpylsuccinamide,

N- Z-dimethylaminoethyl -a.-phenyl-a-n-propylsuccinimide,

N- [3- N '-methyl-N'-ethoxyethylamino -propyl] a-phenyl-a-propylsuccinamide,

N- [4- N-methyl-N'-hydroxyethylamino butyl] a-phenyl-a-allylsuccinamide.

One object of the present invention is to provide new derivatives which are stable and possess valuable pharmacological properties. They are especially useful as local anaesthetics.

Another object of the present invention relates to the preparation of compositions suitable for manufacturing and which are to be administered to animals, including man.

For the preparation of the compounds according to the invention the following general reaction may be used,

wherein R and R have the meaning described above and A is an amino group selected from the class consisting of wherein R is a hydrogen atom or a lower straight or branched alkyl group, R is a hydrogen atom, a hydroXy or lower straight or branched alkoxy group and m is 1-4 in cases when R is a hydrogen atom, or 2, 3 or 4 in cases when R is a hydroxy or lower alkoxy group, which amino group may be present at the reaction or introduced later in a manner known per se and where X, Y and Z are members of the group consisting of OH, Oalk, Hal, NH Otosyl and which are capable of reacting in an arbitrary order with each other with the formation of a N-bridge, whereafter Am in cases when A not is equal to Am, is transferred into Am in a manner known per se. Thus, for instance, X and Y may first react with each other with the formation of an Obridge (an anhydride is formed) or a NH-bridge (a cyclic imide is formed). This will be further illustrated by the examples given below.

The best method for the preparation of the compounds according to the invention consists in reacting preferably equivalent amount of a dicarboxylic acid or its anhydride with an alkylene diamine in accordance with the following general scheme:

(III) 3 4 where R R and A have the meaning given above. phuric acid, organic acids such as acetic, glycolic, lactic, Other methods for the preparation of the compounds levulinic, citric, fumaric, maleic, succinic, tartaric, benzoic according to the invention may be represented by the and cinnamic acids and sulphonic acids, such as methanefollowing reaction schemes: sulphonic and sulphamic acid.

Am=NH X=Halogen Q t? 200C @wn NH;/12Am N-R-Am R] O R; a i r 200C NH H0RAm N-R-Arn 1 NaO ona on on NH NRAn1 2) XRAm R; (I) R;

(R=saturated alkyl) 1) NaOC H /C2E5OH AmH NH W-e RX NRAm R1 \l R1 R1 a c!) O o NHg-R-OH M 1) TosCl Q 0 -R-OH -RAm Q/ 2 ArnH R1 1 6 RI 1 O O t r E i NH2RNHQ /Y (R=saturated alkyl) H /kat. BA 1 R 3 The choice between the different methods of prepare. In therapy the compounds according to the method are tion is affected by the structure of the compound to be administered in the form of a solution in a pharmaprepared, i.e. whether a monoor dialkylamino derivaceutical carrier. The concentration is not important and tive is to be prepared. widely varying concentrations are therapeutically efiec- The compounds according to the invention may occur tive. Typically, solutions may contain from about 0.02% in stereoisomeric forms or even in pairs of enantiomorup to as high as about 10% by weight of the active subphes. This is due to the presence of one or more asymstance. The compounds according to the invention may metric carbon atoms in the molecule. The present invenbe administered in the form of other pharmaceutical tion comprises the optically pure forms as well as mixtures of them.

preparations such as suspensions, jellies, ointments or bases. In these preparations the compounds may be used It has now been found that the compounds according in the form of free bases or as addition salts or as both. to the invention possess valuable pharmacological prop- As is well known in the art, solutions of local anaerties, especially they are active as local anaethetics. As esthetics may be made isotonic by the addition of La. such some of the compounds may be used for topical sodium chloridev Furthermore it is known in the art of anaesthesia while others may favourably be used for inlocal anaesthesia, that the anaesthesia eifectiveness may filtration anaesthesia with an often longlasting effect. be improved by addition of a vascoconstrictor such as These advantages are obtained by the use of one or adrenaline, noradrenaline or octapressin. more compounds selected from the defined group consist- The amount of local anaesthetic which may be used ing of alkylaminoalkyl derivatives of succinimides and varies Widely, as is well known, depending upon the locapharmaceutically acceptable salts thereof. The expression 60 tion and type of anaesthesia required. The anaesthetic pharmaceutically acceptable salts is recognized in the effect, according to the present invention, is induced by art to designate an acid addition salt which is physiologiapplying an amount of alkylaminoalkyl derivative of mcally innocuous when administered in a dosage and at phenyl-a-alkyl-succinimide solution, which is eifective to an interval (i.e., frequence of administration) that is produce the desired anaesthesia. Repeated applications at effective for the indicated therapeutic use of the parent therapeutically eifective intervals may be made, if desired, compound. to obtain a prolonged anaesthetic effect.

Typical therapeutically acceptable addition salts of the These compounds are most conveniently prepared by derivatives of succinimides of the present invention inmixing equimolar amounts of the diacid or its anhydride elude but are not limited to the salts of mineral acids, With the appropriate amine and heating at 160l70 C. such as hydrochloric, hydrobromic, phosphoric or sulfor 1-2 hours. The reaction mixture is distilled and the product obtained is either redistilled or converted to its hydrochloride. For a further understanding of this invention references may be given to the following examples:

EXAMPLE 1 N- 3- [N-methyl-N'-hydroxyethylamino] -propyl) -aphenyl-wpropylsuccinimide 4.36 g. (0.02 mole) of a-phenyl-ot-propylsuccinic anhydride and 2.64 g. (0.02 mole) of 3-(N'-methyl-N'-hydroxyethylamino)-propylamine were mixed and heated on an oil bath at 165 C. for 1.5 hours. Two distillations afforded 4.14 g. of product, b.0 3 180 C. and having the formula 0 @H 0 H2 CH 0 HZN/ C2H4.OH Compounds prepared in accordance with the method, described above are listed in the following Table I which also gives melting points and analytical data.

ing the succinic acid, the antipodes of which are then coupled with the appropriate amine. The latter method is illustrated for the preparation of the antipodes of one compound, falling within the scope of the present invention.

EXAMPLE 3 Resolution of a-phenyl-u-allylsuccinic acid 45.6 g. (0.195 mole) of a-phenyl-a-allylsuccinic acid and 83.9 g. (0.195 mole) of brucine (containing two moles of water of crystallization) were dissolved by heating in 550 ml. of 90% alcohol. The solution was allowed to reach room temperature and was then placed in a refrigerator over night. The salt obtained (63.2 g.) was recrystallized from the same solvent four times, whereupon TABLE I.NALKYLAI\HNOALKYL-a-PHENYL-A-ALKYLSUCCINIMIDES OF THE FORMULA R1 NR Am Analyses M.p. of hydro- Calculated Found chloride or b.p./mrn. Hg Percent Percent M01. Percent Percent M01 Number R R Am of free base N Weight N 01 weight 1- Allyl (CH2)3N(CH3)2 133-5 0 8. 33 10. 53 8. 28 10. 6 2 (l0 -(CH2)3-N(C2H5)z 125 C./0.005 8. 53 8.

3-A .-do CH 143.5-" C 7. 40 9. 63 7. 40 9. 64 3-3 (1O 4; {125 C./0.005 8. l8 8. 23

CH2CH2 5)2 E 4 (l0 -(CH2)aNCHz-CH;OH 140-5 C./0.04 8. 48 330. 4 8. 54 331 /CH3 5 do -(CH2) N 180 C./0,03 8. l4 344. 5 8. 24 342 0 Hz C 112- O H 6 n-Propyl (CHe)2N(CHa)2 7 d0 (CH2)3N(C2H5)2 3 "d0 -(CH2)4N(C2H5): E 9 (lO -CII2'C1'I2CHN(C2H5)3 110 C./0.005 8.13 8. 11

([)H 10 d0 (CH2)2NCH2CHg-OH 175 C./0.[l 8.79 318.4 8.61 31.7

i 11 "(l0 (CHz) 3N CH2 CII2OII 180 C./0.03 8.43 332.5 8. 55 335 5 13 d0 (CH2) .rNCHgCH -OH 185 C./0.03 9. 08 346. 5 8. 22 349 EXAMPLE 2 salt had crystallized. The acid from this salt had a specific rotation [041 +5 1 From the mother liquor the re- (z'dlmethylammoeigfl i maining acid was isolated and recrystallized from ligroin- SUCCI 1ml 6 ethyl acetate until constant rotation was obtained, in all four times. Yield 6.3 g., M.P. l37.540 C.,

[]D28=+64-1 (95% alcohol) and -v -phenyl-a-propylsuccinic acid These were obtained from the enantiomers of a-phenyla-allylsuccinic acid by hydrogenation at room temperature and atmospheric pressure over 10% Pd/ C in alcohol. The direction of rotation is not altered by the hydrogenation. The antipodes had M.P. 14952,5 C. [from ligroin-ethyl acetate and [a] =+resp. -1.5 alcohol) From the optically active acids the corresponding N- amino-alkylsubstituted imides were obtained in the manner already described.

Some of the enantiomers prepared are described in the following Table 2.

TABLE 2.ENANTIOMERS OF N-AMINOALKYL-a-IHENYL-a-ALKYLSUCOINIMIDES OF THE FORMULA 1 Gal...

Analyses I 1 a Cale. Found l1 M.p. of hydrochloride or (957 M01. Percent M01. Percent Number R --B -Am b.p. of free base alcohol) weight 01 weight 01 l45150l0.005 mm. Hg 17 328. 4 323 (CHEM-M0592 {1%fi5:0l0.005 mm. Hg.-- 4 328.4 325 r (OH?) TN(OH3)3 12 .3 +4 3 10 92 1L 0 175-s0 0.o1 mm. Hg -1e 332. 5 332 (GHQPN 175-so 0.o1 mm. Hg +1s 332. 5 332 CHrCHz-OH The succinic acids used for the preparation of succinimides were synthesized by means of known methods as is further illustrated in the following example.

EXAMPLE 4 Q-cm-on K Ho 2 0 The corresponding anhydrides were easily obtained from the acids by refluxing in tetrachloroethane under a water separator.

a-Phenyl on allylsuccinic acid, M.P. 1333.5 C. C H O mol. weight calc. 234.3; found 232. Anhydride Br... 116-7" 0.

C H O calc. (percent): C,72.21; H, 5.59; O, 22.20. Found (percent): C, 71.9; H, 5.58; O, 22.4.

a-Phenyl 0r. propylsuccinic acid, M.P. 146.59 C. C H O mol. weight calc. 236.3; found 233. Anhydride B.P. 128-30" C.

C H O calc. (percent): C, 71.54; H, 6.47; O, 21.99. Found (percent): C, 71.6; H, 6.75; 0, 21.9.

The preparation of succinimides which may be used as starting materials for reactions 1, 2, 3 and 5 related in column 3 is illustrated in the following example.

EXAMPLE 5 ot-Phenyl-a-propylsuccinimide 5.3 g. of a-phenyl u prop-ylsuccinic anhydride were dissolved in 10 ml. of cone. aq. ammonia. The mixture was slowly heated up to 200 C. to distill oif the water and then kept at this temperature for 2 hours. The resulting reaction mixture was directly distilled to yield 3.9 g. of product B. 140-145 C. The IR-spectrum showed peaks characteristic of imide absorption at 1700 and 1760 cm.* (C=0) and at 3400 cm.- (NH).

The compounds described in the above examples and Tables 1 and 2 have also been tested as to their anesthetic properties. The results from these tests have been tabuas measured on isolated fog sciatic nerve and rabbit cornea are based on Lidocaine as standard.

TABLE 3 Isolated frog sciatic nerve l (Lidocaine=l.0)

Toxicity, l.v., ao Ina/ white mouse Rabbit cornea (Lidocaine 1.0)

Compound number Lidocaine I:

(lgigalzfi'g, A.. Truant, A. P. and McOawley, E. L., Yale J. B101. Med. 21

2 Wledllng, 5., Acta Pharmacol. et toxicol. 8 (1952) 117.

EXAMPLE 6 Injecta'ble solution containing N-(3-diethylaminopro pyl) -a-phenyl-a-al1yl succinimide.

To ml. of hot, sterilized water 0.1 g. of methyl p-hydroxybenzoate, 2 g. of N (3 diethylaminopropyl)- a phenyl a allyl succinimide hydrochloride and 0.6 g. of sodium chloride were added in the same way as described in Example 6, but the solution was protected from air-oxygen by working in nitrogen atmosphere. 0.05

g. of sodium pyrosulphite was then dissolved, whereafter 1 mg. of adrenaline was added. pH was adjusted to 4 by adding sodium hydroxide and sterilized water was added to 100 ml.

EXAMPLE 8 Pharmaceutical jelly containing N-(4-diethylaminobutyl) -u-phenyl-a-n-propyl succinimide.

To 80 ml. of distilled water 0.5 g. of -N-(4-diethylaminobutyl) on phenyl a n propylsuccinimide hydrochloride was added. To this solution 4 g. of methylcellulose was added while stirring and when all methylcellulose was dissolved a solution of 50 mg. of chlorohexidine diglyconate in 10 ml. of water was added and the volume was adjusted to 100 ml. by addition of distilled water.

EXAMPLE 9 Pharmaceutical ointment containing N-(Z-diethylaminoethyl)-a-phenyl-ot-n-propyl succinimide.

Equal amounts (27 g. of each) of polyethyleneglycol 300 and polyethyleneglycol 1540 were melted together with 19 g. of polyethyleneglycol 3000 at 60 C. Then 25 g. of propyleneglycol and finally 2 g. of N-(2-diethylaminoethyl)-a-phenyl-a-n-propyl succinimide were added and the ointment was homogenized.

It will be understood that the foregoing examples are for exemplary purpose only, and that the present invention includes many modifications not specifically illustrated. Accordingly the scope of this invention is not to be limited, except as in consistent with the following claims.

In the specification and the claims the expression lower alkyl and lower alkoxy groups refer to groups containing not more than four carbon atoms.

What is claimed is:

1. A pharmaceutical preparation for inducing local anesthesia containing as an active ingredient an amount elfective to induce anesthesia of a compound of the formula or therapeutically acceptable salts thereof, wherein R is selected from the group consisting of saturated and unsaturated straight and branched chain lower alkyl groups having 3 carbon atoms, R is selected from the group consisting of divalent saturated and unsaturated straight and branched chain hydrocarbon radicals containing 2 to 4 carbon atoms, and Am is an amino group of the formula:

wherein R is selected from the group consisting of hydrogen, methyl and ethyl, and R is selected from the group consisting of hydrogen and hydroxy, and m is 1 to 4 when R is hydrogen and 2 to 4 when R is hydroxy, said compound being in association with a pharmaceutically acceptable carrier.

2. The pharmaceutical preparation according to claim 1 wherein said compound is dissolved in sterile, injectible liquid.

3. The pharmaceutical preparation according to claim 1 containing between about 0.02 percent and percent by weight of said compound.

4. The pharmaceutical preparation according to claim 1 containing in addition a vasoconstrictor in an amount 10 elfective to increase the anesthetic effectiveness of said compound.

5. A method for inducing local anesthesia, comprising administering to a host to be anesthetized an effective amount of at least one compound of the formula or therapeutically acceptable addition salts thereof, wherein R is selected from the group consisting of saturated and unsaturated, straight and branched alkyl groups containing 3 carbon atoms, R is selected from the group consisting of divalent saturated and unsaturated straight and branched chain hydrocarbon radicals containing 2 to 4 carbon atoms, and Am is an amino group having the formula wherein R is selected from the group consisting of hydrogen, methyl and ethyl, and R is selected from the group consisting of hydrogen and hydroxy, and in which m is 1 to 4 where R is hydrogen and 2 to 4 when R is hydroxy.

6. A method according to claim 5 wherein said compound is administered by infiltration.

7. A method according to claim 5 wherein said com pound is administered by topical application 8. A method according to claim 5 wherein said compound is N-(Z-dimethylamino ethyl)-a-phenyl-a-n-propyl succinimide or its therapeutically acceptable acid addition salts.

9. A method according to claim 5 wherein said compound is N [N methyl N hydroxyethylamino1- propyl)-a-phenyl-a-n-propyl succinimide or its therapeutically acceptable acid addition salts.

10. A method according to claim 5 wherein said compound is N (3 [N' methyl-N-hydroxyethylamino]- propyl)-ot-phenyl-a-allylsuccinimide or its therapeutically acid salts.

11. A method according to claim 5 wherein said compound is N- 4- [N-methyl-N-hydroxyethylamino] -butyl u-phenyl-a-allylsuccinimide or its therapeutically acceptable acid addition salts.

12. A method according to claim 5 wherein said compound is N (3 diethylaminopropyl) or phenyl-u-npropylsuccinimide or its therapeutically acceptable acid addition salts.

13. A method according to claim 5 wherein said compound is N (3 diethylaminobutyl) a-phenyl-u-allylsuccinimide or its therapeutically acceptable acid addition salts.

14. A method according to claim 5 wherein said compound is N (3 dimethylaminopropyl)-a-phenyl-a-allylsuccinimide or its therapeutically acceptable acid addition salts.

15. A method according to claim 5 wherein said compound is N (3 diethylaminopropyl)-a-phenyl-a-allylsuccinimide or its therapeutically acceptable acid addition salts.

16. A method according to claim 5 wherein said compound is N-(3-diethylaminobutyl)-ot-phenyl-a-n-propylsuccinimide or its therapeutically acceptable acid addition salts.

17. A method according to claim 5 wherein said compound is N (2 methyl hydroxyethylamino ethyl)-u- 1 1 phenyl-u-n-propylsuccinimide or its therapeutically acceptable acid addition salts.

18. A method according to claim 5 wherein said compound is N (4 diethyla-minobutyl)-a-phenyl-a-propylsuccinimide or its therapeutically acceptable acid addition salts.

19. A method according to claim 5 wherein said compound is N (4 [N methyl-N'-hydroxyethylamino]- butyl) oz phenyl u n-propyl succinimide or its therapeutically acceptable acid addition salts.

References Cited UNITED STATES PATENTS ALBERT T. MEYERS, Primary Examiner 10 D. M. STEPHENS, Assistant Examiner mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORREC'IION Patent 3,636,221 Dated January 18, 1972 Inventor(s) Rune Verner Sandberq It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 1, line 36 and Col. 2, lines 42 & 43, "Am" (each occurrence) should be -Am-. I

Col. 2, Diagram III (bottom) the carbonyl group (B) is missing from the right-hand ring of the formula:

(III) Col. 3, line 5, "Am=NH should be -Am;NH

Col. 3, line 58, "anaethetics" should be -anaesthetics-. Col. 6, Table I, last line under heading "Percent N" reads "9.08 should be 8. 09--.

Col. 5, Table 1, Title, "A" should be -OL--. Col. 7, line 71, "B. should be -b Col. 9 line 55, "of the formula" should be --having the formula. Col 10, line 21, "having the formula" should be --of the formula-. Col. 10, line 44 "N- [N' -methyl-N'hydroxyethylamino]propyl) phenyl-cx-m-propyl" should be -N- (3- [N'methyl-N' hydroxy ethyl amino] propyl) oL-phenyl-0c-npropyl-.

Signed and sealed this 26th day of September 1972.

i (SEAL) Attest:

EDWARD M.FLETCHER,JR ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

